Process for preparation of 3-piperazinylbenzisothiazoles

ABSTRACT

There is disclosed a process for preparing 3-piperazinylbenzisothiazoles comprising reacting the specified 3-halo-1,2-benzisothiazole or 2-cyanobenzenesulfenyl halide in the presence of an alkylene glycol derivative. The process is industrially effective, easy and economical and can provide useful intermediates for production of pharmaceutical preparations.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional of application Ser. No. 08/938,845 filed Sep. 26,1997 now U.S. Pat. No. 5,861,511.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing3-piperazinylbenzisothiazoles which are useful compounds as anintermediate for production of pharmaceutical preparations.

BACKGROUND OF THE INVENTION

For preparing 3-piperazinylbenzisothiazole derivatives, mainly twoprocesses have been hitherto known. One of them is a process by reacting3-halo-1,2-benzisothiazole with a piperazine compound according to thefollowing reaction scheme (1): ##STR1## (JP-A 63-83067; JP-A 63-83085;EP-A 196096; J. Chem. Soc., Perkin. Trans., 1(8), 2141. 1988; Ger.Offen., 3530089; J. Med. Chem., 29(3), 359, 1986), and the other one isa process which is disclosed in JP-A 8-291134 which was previously filedby the present applicant, according to the reaction scheme (2): ##STR2##wherein X represents Cl or Br, and R represents H, alkyl group having 1to 6 carbon atoms or substituted alkylene group having 1 to 6 carbonatoms.

OBJECTS OF THE INVENTION

However, the above known techniques require a largely excessive amountof piperazine and very long reaction time and leads to low yield and,thus, they can not be said to be industrially effective processes.

Like this, it was difficult to industrially effectively prepare3-piperazinylbenzisothiazoles by any known process.

Accordingly, the object of the present invention is to provide anindustrially effective process for preparing3-piperazinylbenzisothiazoles.

This object as well as other objects and advantages of the presentinvention will become apparent to those skilled in the art from thefollowing description.

SUMMARY OF THE INVENTION

In view of the above circumstances, the present inventors studiedintensively in order to provide an easy process for economicallyeffectively preparing 3-piperazinylbenzisothiazoles. As a result, wefound that, in a reaction for preparing 3-piperazinylbenzisothiazoles byreacting 3-halo-1,2-benzisothiazole or 2-cyanobenzenesulfenyl halidewith a piperazine compound, when the reaction is performed in thepresence of an alkylene glycol derivative, the advantages such asreduction in an amount of piperazine to be used, improvement in yieldand reduction in reaction time can be shown.

Mechanism therefor is not clear but this may be because the alkyleneglycol derivative manifests the phase transfer catalyst-like activityand enhances the solubility of the piperazine compound in a reactionsystem.

That is, the present invention was done based on such new findings andprovides an economically effective process for preparing3-piperazinylbenzisothiazoles represented by the general formula (IV):##STR3## wherein R₁ represents hydrogen, or alkyl group or substitutedalkylene group each having 1-6 carbon atoms, which comprises:

reacting 3-halo-1,2-benzisothiazole represented by the general formula(I): ##STR4## wherein X represents Cl or Br, or 2-cyanobenzenesulfenylhalide represented by the general formula (V): ##STR5## wherein X is asdefined above, with a piperazine compound represented by the generalformula (II): ##STR6## wherein R₁ is as defined above, in the presenceof an alkylene glycol derivative represented by the general formula(III): ##STR7## wherein R₂ and R₃ each represent hydrogen, or linear orbranched alkyl group having 1 to 4 carbon atoms, and n represents 2-4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be explained in detail below.

The 3-halo-1,2-benzisothiazole used in the present invention isrepresented by the general formula (I) and embodiments thereof are3-chloro-1,2-benzisothiazole, 3-bromo-1,2-benzisothiazole and the like.

The 2-cyanobenzenesulfenyl halide compound which can be used in thepresent invention in addition to the above 3-halo-1,2-benzisothiazole isrepresented by the general formula (V) and can be easily obtained byhalogenating a 2-cyanophenylthio derivative according to a processdescribed in JP-A 8-291134 which was filed by the present applicant, andembodiments thereof are 2-cyanobenzenesulfenyl chloride,2-cyanobenzenesulfenyl bromide and the like.

The piperazine compound used in the present invention is represented bythe general formula (II) and examples thereof are piperazine,1-alkyl-piperazines such as 1-methyl-piperazine, 1-ethyl-piperazine,1-n-butyl-piperazine and the like, 1-substituted alkylene-piperazinessuch as 1-imidobutylene-piperazine, 1-amidobutylene-piperazine,1-((5-indole)ethylene)-piperazine and the like. Particularly, piperazineis preferably used.

An amount of the piperazine compound to be used is in a range of 1 to 10moles, preferably 2 to 4 moles relative to 1 mole of3-halo-1,2-benzisothiazole represented by the general formula (I) or2-cyanobenzenesulfenyl halide represented by the general formula (V).

Further, the alkylene glycol derivative used in the present invention isrepresented by the general formula (III) and examples thereof areethylene glycol, propylene glycol, ethylene glycol monomethyl ether,ethylene glycol monoethyl ether and the like. Particularly, ethyleneglycol is preferably used.

An amount of the alkylene glycol derivative to be used is in a range of0.1 to 10 parts by weight, preferably 0.5 to 5 parts by weight relativeto 1 part by weight of 3-halo-1,2-benzisothiazole represented by thegeneral formula (I) or 2-cyanobenzenesulfenyl halide represented by thegeneral formula (V).

When the amount of the alkylene glycol derivative to be used is belowthis range, its effect is not manifested and, when the amount exceedsthis range, its effect is no longer manifested, conversely leading todisadvantages on reaction operations.

3-Piperazinylbenzisothiazoles which are an end product in the presentinvention are represented by the general formula (IV) and embodimentsthereof are 3-(1-piperazinyl)-1,2-benzisothiazole,3-(4-ethyl-l-piperazinyl)-1,2-benzisothiazole,3-(4-n-butyl-l-piperazinyl)-1,2-benzisothiazole,3-(4-cyclohexyl-1-piperazinyl)-1,2-benzisothiazole and the like.Alternatively, these compounds may be isolated as a salt of a mineralacid such as hydrochloride and sulfate under the acidic conditions inthe presence of hydrochloric acid, sulfuric acid or the like.

A reaction temperature in the process for preparing3-piperazinylbenzisothiazoles as described is normally in a range ofabout 70 to about 150° C., preferably about 100 to about 130 ° C. Whenthe reaction temperature is lower than 70° C., the reaction rate becomesslow. On the other hand, when the reaction temperature is higher than150° C., the side reaction occurs, causing reduction in yield.

A solvent is not necessarily required for a reaction and a non-solventreaction is preferably used although the reaction may be performed in asolvent. In this case, examples of the solvent to be used arehydrocarbons such as cyclohexane and heptane, aromatic hydrocarbons suchas benzene, toluene, xylene, chlorobenzene, dichlorobenzene andtrichlorobenzene, polar solvents such as N,N-dimethylformamide anddimethyl sulfoxide. Normally, the amount of them to be used is, but notlimited to, 0.1 to 10 parts by weight relative to 1 part by weight of3-halo-1,2-benzisothiazole represented by the general formula (I) or2-cyanobenzenesulfenyl halide represented by the general formula (V).

The thus obtained 3-piperazinylbenzisothiazoles represented by thegeneral formula (IV) may be easily isolated and purified from thereaction mixture according to a conventional method such ascrystallization or the like.

Surprisingly, by using the process of the present invention,3-piperazinylbenzisothiazoles which are an end product can be obtainedin about 1/2 to 1/12 reaction time, at about 1/2 to 1/6 amount of thepiperazine compound, and a higher yield by about 20% to 50% as comparedwith the previous processes.

EXAMPLE

The following Examples further illustrate the present invention but arenot to be construed to limit the scope thereof.

Example 1

215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g ofethylene glycol were placed in a four-neck 1000 ml flask equipped with astirrer, a thermometer, a dropping funnel and a condenser, 169.5 g (1.00mol) of 3-chloro-1,2-benzisothiazole was added dropwise in the meltedstate at about 120° C. over 1 hour while stirring, which was thereafterstirred for 2 hours to complete the reaction. After excess piperazinewas removed with water, the reaction mixture was made acidic withhydrochloric acid, extracted into an aqueous layer, which was madealkaline with aqueous sodium hydroxide to obtain 202.4 g (m.p. 89-90°C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from3-chloro-1,2-benzisothiazole was 92.4%.

Example 2

215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g ofethylene glycol were placed in a four-neck 1000 ml flask equipped with astirrer, a thermometer, a dropping funnel and a condenser, 214.1 g (1.00mol) of 2-cyanobenzenesulfenyl chloride was added dropwise in the meltedstate at about 120° C. over 1 hour while stirring, which was thereafterstirred for 2 hours to complete the reaction. After excess piperazinewas removed with water, the reaction mixture was made acidic withhydrochloric acid, extracted into an aqueous layer, which was madealkaline with aqueous sodium hydroxide to obtain 199.5 g (m.p. 89-90°C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from2-cyanobenzenesulfenyl chloride was 91.1%.

Comparative Example 1

304.2 g (3.53 mol) of piperazine, 7.5 g of chlorobenzene, 39.8 g (0.235mol) of 3-chloro-1,2-benzisothiazole were placed in a four-neck 1000 mlflask equipped with a stirrer, a thermometer, a dropping funnel and acondenser, which was heated to stir at about 120° C. for 20 hours. Afterexcess piperazine was removed with water, the reaction mixture was madeacidic with hydrochloric acid, extracted into an aqueous layer, whichwas made alkaline with aqueous sodium hydroxide to obtain 24.4 g (m.p.89 to 90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals.Yield from 3-chloro-1,2-benzisothiazole was 47.4%.

Comparative Example 2

86.2 g (1.00 mol) of piperazine and 7.5 g of chlorobenzene were placedin a four-neck 500 ml flask equipped with a stirrer, a thermometer, adropping funnel and a condenser, 53.5 g (0.25 mol) of2-cyanobenzenesulfenyl chloride was added dropwise in the melted stateat about 130° C. over 1 hour while stirring, which was thereafterstirred for 4 hours to complete the reaction. After excess piperazinewas removed with water, the reaction mixture was made acidic withhydrochloric acid, extracted into an aqueous layer, which was madealkaline with aqueous sodium hydroxide to obtain 40.9 g (m.p. 89 to 90°C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from2-cyanobenzenesulfenyl chloride was 74.7%.

What is claimed is:
 1. A process for preparing3-piperazinylbenzisothiazoles represented by the general formula (IV):##STR8## wherein R₁ represents hydrogen, or alkyl group having 1 to 6carbon atoms, which comprises:reacting 3-halo-1,2-benzisothiazolerepresented by the general formula (I): ##STR9## wherein X represents Clor Br, with a piperazine compound represented by the general formula(II): ##STR10## wherein R₁ is as defined above, in the presence of analkylene glycol derivative represented by the general formula (III):##STR11## wherein R₂ and R₃ each represent hydrogen, or linear orbranched alkyl group having 1 to 4 carbon atoms, and n represents 2 to4.
 2. The process according to claim 1, wherein the piperazine compoundrepresented by the general formula (II) is piperazine.
 3. The processaccording to claim 1, wherein 3-piperazinylbenzisothiazole representedby the general formula (IV) is 3-(1-piperazinyl)-1,2-benzisothiazole. 4.The process according to claim 1, wherein the alkylene glycol derivativerepresented by the general formula (III) is ethylene glycol.